Chemotherapeutic compositions containing n&#39;-cyano-phenyl-triazenecarbox-amidines and method of administering the same



United States Patent 3,313,690 CHEMOTHERAPEUTIC COMPOSITIONS CONTAIN- ING N CYANO PHENYL-TRIAZENECARBOX- AMIDINES AND METHOD OF ADMINISTERING TIE SAME Adolph Whitten Vogel, Pearl River, N.Y., and Robert Allis Hardy, Jr., Ridgewood, and Charles Frederick Howell, Upper Saddle River, N.J., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed June 11, 1964, Ser. No. 374,271 17 Claims. (Cl. 167-65) This invention relates to compositions and methods of utilization thereof. More particularly, it relates to pharmaceutical compositions containing active anti-inflammatory agents and their use.

It is well known that many organic compounds belonging to the steroid field have anti-inflammatory activity. Among these prednisone, prednisolone, triamcinolone, etc., have been used for a number of years. However, there are usually inherent undesirable side eilects particularly when used over a prolonged period of time.

We have now found that pharmaceutical compositions containing as active anti-inflammatory agents N-cyanoaryl-triazenecarboxamidine derivatives are highly useful. The active components of the compositions may be illustrated by the following formula:

R 2 HZ wherein R, R and R" are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkylmercapto, lower alkyl and trilluoromethyl, R is selected from the group consisting of hydrogen and lower alkyl and their pharmaceutically acceptable salts.

The triazenecarboxamidines of this invention are highly useful anti-inflammatory agents. They show excellent anti-inflammatory action at very low doses and possess distinct advantages over other non-steroid antiinflammatory drugs such as the salicylates and phenylbutazone. The spread between the efifective dose and the lethal dose is advantageously very large, with ratios of lethal to effective doses of about 100 to 1000 for representative compounds of this invention. The valuable anti-inflammatory properties of the compounds of this invention are readily demonstrated since they markedly reduce the size of a subcutaneous carrageenin-induced infiammatory granuioma. The active compounds of this invention may be used as the free substance or as nontoxic salts. They are generally administered orally or locally, and when so administered may be considered anti-inflammatory agents for the therapeutic treatment of rheumatoid diorders and other inflammatory conditions at individual doses ranging from about 5 to about 300 milligrams. The dosage regimen can be adjusted to provide optimum therapeutic response. Thus, for example, several doses may be administered daily, or the dose may be reduced proportionately as indicated by the exigencies of the therapeutic situation. It is also possible to adjust the dosage regimen so that individual doses are given intermittently at intervals of from several days to about a week or more with maintenance of an effective level of anti-inflammatory action. The active compositions of this invention may also be considered therapeutically useful by parenteral administration such as local injection into the inflamed area. For example, they may be administered by intra-articular injection into an inflamed joint. Other examples of parenteral routes for the therapeutic administration of the compounds of this 3,313,690 Patented Apr. 11, 1967 invention include intramascular and intravenous administration of solutions and/ or suspensions.

Due to the mobility of the hydrogen atoms, it is likely that these compounds may also exist in a variety of additional tautomeric forms which may change under the influence of different solvents, degree of acidity, and conditions for crystallization. For example, the preferred tautomeric form for the sodium salt of 1-aryl-N'-cyano- 3-triazenecarboxamidines in methanol is shown:

It is to be understood that the present invention includes within its scope the above compounds as active therapeutic compositions in all such tautomeric forms.

The active compounds of this invention may exist in several forms. For example, as the free acids they are generally white, crystalline solids which are insoluble in water and sparingly soluble in organic solvents. The free acids are unstable when heated, When irradiated with ultra-violet light and when treated with mineral acids. They form salts with alkali and alkaline earth metal bases such as hydroxides and alkoxides. These metal salts are generally yellow, crystalline solids which are more stable to heat than the free acids and are somewhat more soluble in water. The free acids also form salts with strong organic bases such as choline and the like.

The compositions of the present invention are preferably presented for administration in unit dosage form as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions and the like. For preparing solid compositions such as tablets, the principal active ingredient is mixed with conventoinal tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and functionally similar materials as pharmaceutical diluents or carriers. The tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate, and the like. A particularly advantageous enteric coat1ng comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating.

The liquid forms in which the novel composition of the present invention may be incorporated for administration include aqueous solutions and suspensions, suitable flavored syrups, oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil and the like, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatin and the like. Sterile suspensions or solutions are required for parenteral use. Isotonic '1 3 preparations containing suitable preservatives are also highly desirable for injection use.

The term unit dosage form as used in the specification and claims refers to physically discrete units suitable as unitary dosages for animal subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in asociation with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic'etfect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for therapeutic use in animals as disclosed in detail in this specification, these being features of the present invention. Examples of suitable oral unit dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, amples, vials, segregated multiples of any of the foregoing, and other forms as herein described.

The active triazenecarboxamidines of this invention are readily prepared by the method illustrated by the following:

where R, R and R are as previously described and X is halogen and M is an alkali or alkaline earth metal.

By this method a suitable aniline derivative is diazotized and coupled with dicyandiamide in alkaline solution. The resulting N-cy-ano-1-aryl-3-triaZene-carboxamidines may be isolated as the metal salts by salting out or by conversion to the relatively insoluble free acid form.

The following examples describe anti-inflammatory testing, methods of preparing representative compounds of the invention, and pharmaceutical preparations containing representative anti-inflammatory agents.

EXAMPLE 1 Anti-inflammatory screening Groups of two rats each are injected subcutaneously at the midline of the shaved sacral region with 0.5 ml. of a 2% aqueous carrageenin solution. (Carrageenin is a polygalactose sulfate extracted from Irish moss, a type of sea-weed. Subcutaneous injection of carrageenin causes rapid formation of an intense subcutaneous inflammatory reaction which subsequently develops into a connective tissue granuloma.) The compounds of this invention are suspended in aqueous 1% starch-sodium phosphate butter solution; pH 6.5, and administered by oral tubing in 0.5 ml.; the total dose for each animal is 250 rug/kg. of body weight. One-half of each total dose is administered immediately following the carrageenin injection, and the second half of each total dose 4 hours later. Alternately, the total dose for each animal may be injected all at once immediately following the carrageenin injection. The animals are killed 24 hours after the carrageenin injections. The inflammatory reaction to the carrageenin results in the formation of exudate and gelatinous material which is removed and weighed. Control animals receive the carrageenin injection and the starch-sodium phosphate buffer solution orally without the test agent. Critical ratios (C/ T :the ratio of weight of exudate and gelatinous material from control animals to weight of same [.1 from test animals) are calculated, and compared by a 3-stage sequential screening procedure:

The above ratios represent a statistically designed method for detecting anti-inflammatory activity which is significantly different than the variability of control animals at the 95% confidence level. Thus, a compound which on the first stage give a (C/T) =1.11 or below is rejected; if the ratio is between 1.11 and 1.65 the compound is retested; and if the ratio is 1.65 or above the compound is accepted as active. On thesecond stage (re-test because (C/T) is between 1.11 and 1.65), if the product (C/T) (C/T) is 1.49 or below the compound is rejected; if this product is between 1.49 and 2.23 the compound is given a third trial; if 2.23 or above the compound is accepted. On the third stage if the product (C/T) (C/T) (C/T) is less than 2.46 the compound is rejected as inactive; but if this product is 2.46 or above the compound is accepted as an active antiinfiamrnatory agent.

When the compounds of this invention are tested by the above procedure, the following results are obtained.

Product of C/ T Compound: ratios (stage accepted) N cyano 1 phenyl 3 triazenecarboxamidine sodium salt 1.88 (1); 2.17 (l) N cyano 1 (p chlorophenyl) 3 triazenecarboxamidine sodium salt N cyano 1 (p chlorophenyl) 3 triazenecarboxamidine N cyano 3 (p chlorophenyl) 3 methyl 1 triazenecarboxamidine sodium salt N cyano 1 (5 chloro 2- rnethoxyphenyl) 3 triazenecarboxamidine sodium salt N cyano 1 (5 chloro- 2 methylphenyl) 3 triazenecarboxamidine sodium salt N cyano 1 (In chlorophenyl) 3 triazenecarboxamidine sodium salt N cyano 1 (p methoxyphenyl) 3 triazenecarboxamidine sodium salt N cyano 1 (p methoxyphenyl) 3 triazenecarboxamidine magnesium salt N cyano 1 (m trifluoromethylphenyl) 3 triazeneboxamidine sodium salt N cyano 1 (m methoxyphenyl) 3 triazene carboxamidine potassium salt N cyano 1 (p tolyl) 3- triazenecarboxamidine sodium salt 3.08

N cyano 1 (p ethoxyphenyl) 3 triazenecarboxamidine sodium salt 2.51

N cyano 1 (o methoxyphenyl) 3 triazenecarboxamidine sodium salt 2.70

N cyano 1 (p methoxyphenyl) 3 triazeneoarboxand Wilcoxon. The LD is the median lethal dose which causes 50% mortality.

amidine choline salt 1.96 (1); 4.28 (1) The eflfective doses (ED and ED and median lethal N cyano 1 (3,4 dimedoses (LD are compared for a given test agent to thoxyphenyl) 3 triazene- 5 demonstrate that the anti-inflammatory activity is obtained carboxamidine sodium salt 2.67 (l); 3.50 (2) at non-toxic dose levels with a desirably wide spread be- N' cyano 1 (0 trifluorotween the effective and toxic dose levels. An anti-inflammethylphenyl) 3 triazenematory index (ratio of the lethal to the E'D dose levels) carboxamidine sodium salt 3.13 (2); 1.86 (1) may be calculated.

N cyano 1 (o tolyl) 3- When representative active compounds of the present tn'azeneoanboxamidine sodiinvention are evaluated by the above described procedures um salt 1.70 (1); 2.09 (1) the following results are obtained:

Anti- Compound EDzg, ED50, LD 0, inflammatory mg./kg., p.o. mg./kg., p.o. mg./kg., p.o. ex

(LDED/EDZD) N -eyano-l-(S-chloro-Z-methyl phenyl)-3triazenecarboxamidine sodium salt N cyano-1phenyl-3-triazeuecarboxamidiue sodium salt 24 N-cyano-1-(p-methoxyphenyl)-3-triazeneearboxamidine sodium salt 0. 7 N -cyano-1-(p-chlorophenyl)-3-triazenecarboxamidine sodium salt 10 N-cyano-1(otoly1)-3-triazenecarboxamidine sodium salt 33 N -cyano-1-(m-methoxyphenyD-B-triazenecarboxamidine potassium salt- 12.5 N-cyan0-l-(0-methoxyphenyl)-3-triazenecarboxamidine sodium salt 26 N -cyano-1(p-ethoxyphenyl)-3-triazenecarboxamidine sodium salt. 2. 8 N -cyano-l-(rn-chlorophenyl)-3-triazeneearboxamidine sodium salt 10 N '-cyano-1-(5-chloro-21nethoxyphenyl)-3-triazenecarboxamidine sodium sa t. 17 N-cyano-1(m-trifluoromethylphenyl)-3-triazenecarboxamidine sodium salt cyano -(pt0lyl)-3-triazenecarboxarnidine sodium salt 22 Phenylbutazone- 12. 7 250 445 3. 5 Triamcinolone- 3. 5 65 500 140- N' cyano 1 (p methylmercaptophenyl) 3 Lriazenecarboxarnidine sodium salt N cyano 1 (p ethylphenyl) 3 triazenecarboxami- EXAMPLE 2 Anti-inflammatory evaluation The general procedure of Example 1 is repeated. The carrageenin grauuloma is produced in the same manner and the method of administration of the test agents is identical. However, about 5 graded doses of the test agent (accepted as active in the screening procedure and confirmed by replication of the screening procedure) are administered to 4 rats at each dose level. Mean abscess Weights of the control and treated groups are recorded. The entire experiment is replicated three times, the results are subjected to statistical analysis, and a dose-response curve is calculated. This data is used to calculate effective dose levels for relative potency comparisons. For example, the ED is defined as the dose of a test agent which produces a 29% reduction of mean abscess weights compared to the control groups. The 29% reduction of inflammatory response represents the midpoint of the dose-response curve for the anti-inflammatory drug, pheylbutazone, and is used for relative potency comparisons with this drug. An ED is defined as the dose of a test agent which produces a reduction in the subcutaneous inflammatory response to carrageenin as measured by the mean abscess weights. The ED may also be used for relative potency comparisons.

Toxicity: Groups of ten rats each are administered graded doses of the test agent by oral tubing and observed daily for 7 to 14 days. The cumulative number of deaths in each group at each dose level is recorded and this data is used to calculate an LD by the method of Litchfield EXAMPLE 3 Anti-inflan'zmatoly activity by local administration The general procedure of Example 2 is repeated. The

20, 50, Compound mg./kg., mg./kg.,

s.c. s.c.

N-cyano-l-(5-chloro-2-methoxyphenyl)-3-triazenecarboxamidine sodium salt 1. 2 4. 3 N -cyano1-(p-methoxyphenyl) -3-triazenecarboxamidine sodium salt 0. 4 0. 9 N-cyano-1-(p-methoxyphenyl)-3-triazenecarboxamidine magnesium salt O. 9 1. 6 N -eyano-1-(m-methoxyphenyl) -3-triazeneca rboxamidine potassium salt 0.8 1. 9 N-cyano-1-(o-methoxyphenyl)-3-triazenecarboxamidine sodium salt 0. 4 1. 6 N-cyano-1-(p-ethoxyphenyl)-3-triazenecarboxamidine sodium salt 1. 2 2. 2 N -eyan0-1-phenyl-3-triazeneearboxamidine sodium salt 1. 2 2. 0 N cyano-1-(p-chl0rophenyl)-3-triazeneearboxamidine sodium salt 0.7 2. 4 N-cyano-1-(p-t0lyl)-3-triazenecarboxamidine sodium salt 1. 9 3. 6 Phenylbutazone- 30 1, 000 Triamcinolone 2. 5 30 carrageenin granuloma is produced in the same manner, but the test agents are administered subcutaneously into the same site as the carrageenin injection immediately following the carrageenin injection.

Graded doses are administered to 4 rats at each dose level and the 24 hour mean abscess Weights of the control and treated groups are recorded. The results are subjected to statistical analysis, a dose-response curve is calculated and effective dose levels are determined.

When representative active compounds of the present invention are evaluated by the above-described procedure, the following results are obtained:

EXAMPLE 4 Preparation of N -cyan0-I p-methoxyphenyl -3 -triazenecarboxamidine A solution of 12.3 grams of p-anisidine in 22 milliliters of concentrated hydrochloric acid and milliliters of Water is warmed and then cooled quickly in an ice or iceacetone bath to to C. The mixture is treated in the cold with a solution of 7.2 grams of sodium nitrite in milliliters of water, The resulting solution yields a blue-violet color with potassium iodide starch paper indicative of a slight excess of nitrous acid. The solution is treated with charcoal powder and filtered into a solution of 120 milliliters of 10% sodium hydroxide, 10.1 grams of dicyandiamide and 400 milliliters of water. The resulting solution (pH 8-10) is warmed at to C. for /2 to 2 hours until a test sample placed on filter paper no longer gives a red test for diazonium salt with alkaline Rsalt (2-a-mino-8-naphthol 3,6-disulfonic acid). The solution is cooled, treated with charcoal and filtered directly into an ice-cold solution of 182 milliliters of 2 N acetic acid and 700 milliliters of water. The free acid is collected by filtration and pressed dry. It may be purified by dissolving it in a solution of 4.6 grams of lithium hydroxide in 200 milliliters of water charcoaling and filtering into 250 milliliters of 2 N acetic acid. The purified acid is collected by filtration, pressed as dry as possible and mixed with a solution of 10.8 grams of sodium methoxide in milliliters of ethanol. Cooling yields the yellow sodium salt which melts at about 233234 C. with decomposition. This salt is purified by recrystallization from dimethylformamide-ether or from methanol followed by boiling briefly with acetone or acetonitrile to remove traces of solvent.

The magnesium salt is prepared from the sodium salt by treating 2.0 grams of the latter dissolved in 8 milliliters of water with 8.3 milliliters of 2 N acetic acid diluted with 48 milliliters of ice water. The colorless acid precipitates, is collected on a filter and dried thoroughly over phosphorus pentoxide under reduced pressure at room temperature. The acid is suspended in 30 milliliters of absolute methanol under nitrogen, treated with 8 milliliters of 1 N magnesium methoxide in methanol and stirred until the colorless acid has dissolved and the yellow orange salt has separated, The salt is collected by filtration under nitrogen and dried at once over phosphorus pentoxide. The magnesium salt decomposes slowly with no definite melting point between about and 160 C. and rapidly absorbs moisture from the atmosphere.

The choline salt is prepared from the acid by treating a sample with slightly less than 1 equivalent of aqueous 1 M fl-hydroxyethyltrimethylamrnonium hydroxide. The mixture is filtered and the filtrate lyophylized. The residue is recrystallized twice from isopropanol to give yellow platelets of the choline salt which melts at 114-l16 C.

EXAMPLE 5 Preparation of 3- (p-clz iorophenyl) -N-cyzm0-3-me thyl- 1 -triazenecarb0xam idine A solution of 7.3 grams of 1-(p-chlorophenyl)-N- cyano-3-triazenecarboxamidine in ml. of 1 M lithium hydroxide at about 25 C. is treated with 4.7 milliliters of dimethyl sulfate. After being stirred for 30 minutes this mixture is diluted with 50 milliliters of l M lithium hydroxide and filtered. The product is washed thoroughly with water and dried over phosphorus pentoxide under reduced pressure at room temperature. The resulting mixture of isomers is dissolved in 1500 milliliters of methylene chloride and adsorbed into a chromatographic column of grams of l00200 mesh silica gel and eluted with mixtures of methylene chloride and ether until a yellow color due to the desired component appears in the eluate. 3-(p-chlorophenyl)-N'-cyano-3 methyl 1 triazenecarboxamidine is eluted with ether or with a 4:1 (v./v.) methylene chloride-ether mixture until the eluate is no longer yellow. The eluate is concentrated and the product is recrystallized from methanol to give yellow prisms which melt at 181182 C. and are characterized y XCHQOH 331336 ($18,700)

in the ultraviolet spectrum.

EXAMPLE 6 Preparation of N-cyan0-1phenyl- 3 -triazenecarboxamidine The general procedure of Example 4 is repeated. From the diazotization of aniline and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 242-244 C. with decomposition and ultraviolet absorption at no 3 mt when purified by the procedures previously described.

EXAMPLE 7 Preparation 0 N-cyan0-1-(p-chloi'ophenyl) -3- triazcnecarboxamidine Using the procedure of Example 4 and diazotizing pchloroaniline and coupling with dicyandiamide, the above product is obtained as a sodium salt, melting point 247- 248 C. with decomposition and ultraviolet absorption at was 2 mt when purified by the procedures previously described. The free acid is obtained by treating an ice cold solution of 0.5 gram of the sodium salt in 25 milliliters of water with 2 milliliters of 2 N acetic acid. The precipitate is collected and dried in the dark over phosphorus pentoxide under reduced pressure at room temperature. The free acid melts at about 149-151 C. with decomposition and evolution of gas and shows ultraviolet absorption at OH OH r 307 m EXAMPLE 8 Preparation of N-cyan0-1-(5-chloro-Z-methoxyplzenyl)- 3-triazenecarboxamidine When the procedure of Example 4 is repeated with the diazotization of 5-chloro-2-methoxyaniline and coupling with dicyandiamide, the above product is obtained as a sodium salt, melting point 272274 C. with decomposition and ultraviolet absorption at new 3 8 i when purified by the procedures previously described.

EXAMPLE 9 Preparation of N-cyan0-1-(5-011loro-Z-methylphenyl)- 3-triazenecarboxamidine Using the procedure of Example 4 with the diazotization of S-chloro-Z-methylaniline and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 234237 C. with decomposition and ultraviolet absorption at Mi -,1? 231 m when purified by the procedures previously described.

EXAMPLE 10 Preparation of N'-cyano-1-(m-chlorophenyl)- 3-triazenecarb0xamidine When the procedure of Example 4 is used with the diazotization of m-chloroaniline and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 234236 C. with decomposition and ultraviolet absorption at Mkif 337 ru when purified by the procedure previously described.

9 EXAMPLE 11 Preparation of N '-cyano-I m-triflaoromethyl plzenyl 3-triazenecarboxamidine Using the procedure of Example 4 with the diazotization of m-trifiuoromethylaniline and coupling with dicyandiamide, the above product is obtained as a sodium salt, melting point 227 C. with decomposition and ultra violet absorption at itty 332 a when purified by the procedures previously described.

EXAMPLE 12 Preparation of N-cyan-1-(m-methoxyphenyl) 3 -triazenecarboxamidine The general procedure of Example 4 is repeated. From the diazotization of m-anisidine and coupling with dicyandiamide, this product is obtained as a potassium salt, melting point 229230 C. with decomposition and ultraviolet absorption at when purified by the procedures previously described.

EXAMPLE 13 Preparation of N'-cyan0-1-(p-t0lyl) 3-triazenecarb0xamidine When the procedure of Example 4 is used with the diazotization of p-toluidine and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 245 C. with decomposition and ultraviolet absorption at ragg 334 111,11

when purified by the procedures previously described.

EXAMPLE 14 Preparation of N-cyan0-1-(p-ethoxyphenyl)- 3-triazenecarb0xamidine The procedure of Example 4 is repeated. From the diazotization of p-ethoxyaniline and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 243-245 C. with decomposition and ultraviolet absorption at in? 340 m when purified by the procedures previously described.

EXAMPLE 15 Preparation 0 f N '-cyan0-] o-meth oxy plzenyl 3-triazenecarboxamidine Using the procedure of Example 4 with the diazotization of o-anisidine and coupling with dicyandiamide, the above product is obtained as a sodium salt, melting point 230-231 C. with decomposition and ultraviolet absorption at when purified by the procedures previously described.

EXAMPLE 16 Preparation of N -cyan0-] -(3,4-dimethoxypl1enyl 3-triazenecarboxamidine When the procedure of Example 4 is used with the diazotization of 4-aminoveratrole and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 164166 C. with decomposition and ultraviolet absorption at when purified by the procedures previously described.

10 EXAMPLE 17 Preparation of N -cyano-J o-tri fluoromethylphenyl -3 triazenecarboxamidine Preparation of N -cyano-] o-tolyl -3 -triazenecarb0xam idine When the procedure of Example 4 is used with the diazotization of o-toluidine and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 195 C. with decomposition and ultraviolet absorption at r g-55 334 m, when purified by the procedures previously described.

EXAMPLE 19 Preparation 0 f N '-cyan0-] p-meth ylmercaptophenyl -3 triazenecarboxamidine When the procedure of Example 4 is used with the diazotization of p-methylmercaptoaniline and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 258259 C. with decomposition and ultraviolet absorption at xglf 356 III r when purified by the procedures previously described.

EXAMPLE 20 Preparation of N '-cyano-I p-ethylphenyl -3 -triazenecarboxamidine When the procedure of Example 4 is used with the diazotization of p-ethylaniline and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 139141 C. with decomposition and ultraviolet absorption at er 335 i when purified by the procedures previously described.

EXAMPLE 21 Preparation of N -cyano-] 3,4,5 -trimeth0xyphenyl -3 zriazen ecarboxamidine When the procedure of Example 4 is used With the diazotization of 3,4,5-trirnethoxyaniline and coupling with dicyandiamide, this product is obtained as a sodium salt, melting point 157159 C. with decomposition and ultraviolet absorption at it-55 340 u when purified by the procedures previously described.

EXAMPLE 22 Capsules containing N '-cyano-] p-meth oxyph enyl -3 triazenecarb oxam idine Per For Capsule 10,000

(g.) Capsules Active ingredient: N-cya.no-1-(p-methoxy- O. 025 250 ptfiznyl)-3-tnazenecarboxamidine sodium sa Lactose 740 Magnesium stearate (1%) 10 The dry ingredients are thoroughly mixed and 0.100 g. of the mix is placed in each gelatin capsule.

We claim:

1. A chemotherapeutic composition for use in animals as an anti-inflammatory agent which comprises a pharmaceutical carrier and 'a compound selected from the group consisting of N-cyano-aryl-triazenecarboxamidines of the formula:

wherein R, R and R" are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkylmercapto, lower alkyl and trifiuorornethyl, R is selected from the group consisting of hydrogen and lower alkyl and non-toxic pharmaceutically acceptable salts thereof.

2. A chemotherapeutic, anti-inflammatory composition useful in animals which comprises a pharmaceutical carrier and from about to about 300 milligrams of a compound selected from the group consisting of N'-cyanoaryl-triazene-carboxamidines of the formula:

wherein R, R and R" are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkylmercapto, lower alkyl and trifiuoromethyl, R is selected from the group consisting of hydrogen and lower alkyl and non-toxic pharmaceutically acceptable salts thereof.

3. A chemotherapeutic composition in accordance with claim 2 wherein the active component is N'-cyano-1-(5- chloro-Z-methylphenyl) -3 -triazenecarboxamidine.

4. A chemotherapeutic composition in accordance with claim 2 wherein the active component is N'-cyano-l-(pmethoxyphenyl) 3 -triazenecarboxamidine.

5. A chemotherapeutic composition in accordance with claim 2 wherein the active component is N-cyano-1- phenyl-3-triazenecarboxamidine.

6. A chemotherapeutic composition in accordance with claim 2 wherein the active component is N-cyano1-(pchlorophenyl) -3 -triazenecarboxarnidine.

7. A chemotherapeutic composition in accordance with claim 2 wherein the active component is N-cyano-3-(pchlorophenyl)-3-methyl-1-triazenecarboxamidine.

8. A chemotherapeutic, anti-inflammatory composition useful in animals which comprises a pharmaceutical carrier and from about 5 to about 300 milligrams of N'- 12 cyano 1 (m trifluoromethylphenyl) 3 triazenecarboxamidine sodium salt.

9. A method for treatment of inflammatory and rheumatic condition in animals by administering a composition comprising a pharmaceutical carrier and from about 5 to about 300 milligrams of a compound selected from the group consisting of N-cyano-aryl-triazenecarboxamidines of the formula:

wherein R, R and R" are selected from the group conisting of hydrogen, halogen, lower alkoxy, lower alkyl imercapto, lower alkyl and trifiuoromethyl, R is selected from the group consisting of hydrogen and lower alkyl and non-toxic pharmaceutically acceptable salts thereof.

10. A method for treatment of inflammatory and rheumatic conditions in accordance with claim 9 in which the compound is N-cyano-1-(S-chloro2-methylphenyl)-3- triazenecarboxamidine.

11. A method in accordance with claim 9 in which the N-cyano-aryl-triazenecarboxamidine is N'-cyano-1-(pmethoxyphenyl) -3 -triazenecarboxamidine.

12. A method in accordance with claim 9 in which the N-cyano-aryl-triazenecarboxarnidine is N cyano-l-phenyl-3-triazenecarboxamidine.

13. A method in accordance with claim 9 in which the N'-cyano-aryl-triazenecarboxamidine is N'-cyano-1-(pchlorophenyl) -3-triazenecarboxamidine.

14. A method in accordance with claim 9 in which the N'-cyano-aryl-triazenecarboxamidine is N'-cyano-3-(p- .chloropheuyl)-3-methyl-l-triazenecarboxamidine sodium salt.

15. A method in accordance with claim 9 in which the N-cyano-aryl-triazenecarboxamidine is N'-cyano-1-(mtrifiuoromethylphenyl)-3-triazenecarboxamidine sodium salt.

16. A method in accordance with claim 9 in which the N-cyano-aryl-triazenecarboxamidine is N'-cyano-1-(pethoxyphenyl)-3-triazenecarboxamidine sodium salt.

17. A method in accordance with claim 9 in which the N-cyano-aryl-triazenecarboxamidine is N'-cyano-l-(mmethoxyphenyl)-3-triazenecarboxamidine potassium salt.

No references cited.

ALBERT T. MEYERS, Primary Examiner. LEROY B. RANDALL, Assistant Examiner. 

